ASSESSMENT OF GROWTH-HORMONE INSULIN-LIKE GROWTH-FACTOR-I AXIS IN DOWNS-SYNDROME

As GH therapy has been reported to increase growth velocity in childre n with Down's syndrome (DS), we studied the GH-IGF-I axis in some DS p atients affected by growth retardation without serious congenital malf ormation, malnutrition or pathological thyroid or adrenal function. IG F-I and IGF-II were evaluated in 39 patients in basal conditions. The patients were subsequently divided into two groups with respect to the IGF-I basal value: Group 1 (GR 1) consisting of patients with abnorma lly low basal IGF-I concentration as compared to age matched control s ubjects, group 2 (GR 2) consisting of patients with IGF-I in the norma l range. In 6 GR 1 patients and 12 GR 2 patients we evaluated GH and I GF-I concentrations after stimulation with arginine (0.5 g/kg bw), and recombinant GH (4 IU im). In the same patients, GH radioreceptor assa y and serum GH-binding protein were evaluated. In all patients IGF-II proved normal (534+/-23 ng/ml; mean+/-SE), while IGF-I was pathologica l in 36% of subjects. The cause of the defective IGF-I secretion in th ese patients does not seem to depend on an impaired GH axis, as no sig nificant difference in arginine-stimulated GH peak values was seen bet ween GR 1 (29.6+/-5.3 ng/ml) and GR 2 (15.1+/-2.24 ng/ml). IGF-I conce ntration evaluated 12, 24, and 48 h after arginine stimulation was sig nificantly increased only in GR 2 patients (peak value: 0.95+/-0.1, p= 0.0003 vs baseline; GR 1: 0.34+/-0.05 U/ml). By contrast, administrati on of GH produced a rise in IGF-I in both groups; though the mean peak value in GR 1 (0.63+/-0.09 U/ml; p=0.0005 vs baseline) was lower than that in GR 2 (1.07+/-0.1), the size of the increase in relation to th e baseline values was similar in both groups (GR 1: 173+/-29%, GR 2: 8 7+/-16%). In agreement with these findings we have indirectly proved t he presence of GH receptor in the GR 1 patients, and demonstrated thei r normal levels by evaluating the GH-binding protein (DS: 21.5+/-6.8% Bound/Total; controls: 23.6+/-11.8%). On the other hand, the evaluatio n of the GH RRA/IRMA ratio revealed a presence of a reduced bioactivit y of endogenous GH in GR 1 (0.81+/-0.1;GR 2: 1.05+/-0.06), and particu larly in two patients (0.41 and 0.61 respectively). In conclusion, our data suggest that impaired growth in some patients affected by Down's syndrome can be accounted for by a GH molecule that is immunoreactive but not bioactive.